Effect And Underlying Mechanism Of RXR_α Agonist Bexarotene On Cardiac Structure And Function In Diabetic Rats

Aims: To explore the effect and underlying mechanism of bexarotene, the agonist of retinoid X receptor, on the structure and function of the heart in the streptozotocin（STZ）-induced diabetic rats. Meanwhile, Doppler echocardiography was evaluated for early recognition of the heart dysfunction in rats with diabetic cardiomyopathy.Methods:40 SD rats were randomly divided into four groups: group A, normal control group, intraperitoneal injection of citrate buffer（0.1ml/100g）; group B, diabetic group（DM）, intraperitoneal injection of STZ（60mg/Kg）; group C, DM+Bex（10mg/kg /d）; D group, DM + Bex（20mg/kg/d）, 10 in each group. Blood glucose levels was determined by oxidase method, liver function was measured with enzymatic assay, picric acid method was used for the determination of serum creatinine. In our study, conventional echocardiography, quantitative tissue velocity imaging and two-dimensional strain were simultaneous applied to assess cardiac structure and function of diabetic rats. Heart and left ventricular mass, and left ventricular mass index（heart or left ventricular mass/tibia length） were calculated; HE staining was performed to observe the structure changes in rat myocardium; Myocardial apoptosis was detected by Tunnel method, meanwhile, Bax and Bcl2 protein levels were tested by Western blotting.Results:（1） Fasting blood glucose levels in DM group were significantly higher than that in control（25.65 ± 3.75 vs 5.99 ± 0.48 m M, p <0.01）, and there were no significant changes in the succeeding 8 weeks; The blood glucose in DM+Bex（20mg/kg/d） group decreased significantly from baseline after 4 weeks Bex intervention（p <0.01）.（2） Heart weight, left ventricular weight, heart weight/tibial length ratio and left ventricular weight /tibial length ratios were decreased than those in the control group.However, RXRα agonist bexarotene inhibited the effects of DM on these parameters in a dose-dependent manner.（3） IVSd and LVPWd were significantly lower in DM group than that in control group, which was found though conventional echocardiography. But, IVSd and LVPWd were significantly increased in DM+Bex（20mg/kg/d） group compared with DM group（p<0.01）.（4） Ultrasound quantitative tissue velocity imaging results showed that S, S ’, S_ave, e, e’, e_ave, a, a ’ and a_ave in DM group were significant decreased compared with the control. Bex intervention significantly improved S, S’, S_ave, e, e’, e_ave, a, a’ and a_ave in a concentration-dependent manner.（5） Left ventricular longitudinal strain, stratified longitudinal strain and longitudinal strain rate（Sr L） in DM group were significantly declined compared with the controls, while Bex intervention could significantly improve those parameters in a concentration-dependent.（6） Compared with the control group, myocardial apoptosis proteins（Bcl2 and Bax） expression levels and myocardial apoptosis rate were increased significantly in DM group. In contrast, Bcl2/Bax ratio in DM rats was significantly lower than that in controls（p<0.01）; Bexarotene inhibited the impact of diabetes on myocardial apoptosis and apoptosis proteins expression in a dose-dependent manner.Conclusions:（1） The abnormal cardiac structure and function in diabetic rats may be associated with cardiomyocyte apoptosis and ventricular remodeling;（2） RXRα agonists bexarotene improves cardiac structure and function in STZ-induced diabetic rats through lowering blood sugar, inhibition of cardiomyocyte apoptosis and ventricular remodeling;（3） Myocardial longitudinal velocity and two-dimensional strain strain are more sensitive to detect the early abnormality of systolic and diastolic function than conventional two-dimensional echocardiography in STZ-induced diabetic rats.